Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor

项目总结（见说明）; 该提案是原SPORE赠款中项目2的延续。关于这项建议，我们有 通过体外研究、动物实验和动物实验，开发了一种抗DRS单克隆抗体治疗胰腺癌的方法， 模型疗效，并与行业合作伙伴（第一三共），I期和最近完成的II期试验 在胰腺癌中。我们还发现了一种新的分子（DDX 3），它似乎在 调节抗DRS介导的细胞凋亡。在本建议书中，我们会探讨两项策略， 抗DRS单克隆治疗的功效，特别是在胰腺肿瘤细胞系中， 两种策略是评估单克隆抗DR 4试剂的添加或 加入凋亡级联的小分子调节剂。两种凋亡调节剂 评估的是AT-101（Bcl-2家族抑制剂）和AT-406（IAP家族抑制剂）。这两个战略将 使用体外分析和原位和转移性异种胰腺癌模型进行研究 最佳策略的第一阶段试验此外，我们将继续研究DDX 3和 DRS/DDX 3复合物作为肿瘤细胞对死亡受体介导的敏感性/抗性的推定生物标志物 抗肿瘤功效和作为抗DR介导的抗肿瘤作用的增强策略的靶标。

PROJECT SUMMARY (See instructions); This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.